Ring-expanded (Fat) purine nucleosides and nucleotides are of chemical, biochemical, biophysical and medicinal interest. From a chemical standpoint, their synthesis, structure, stability, acid-base properties, aromaticity, and tautomeric equilibria are interesting. From a biochemical perspective, they are an abundant source of substrates or inhibitors of enzymes of purine metabolism, as well as of those requiring energy cofactors. In biophysical terms, they are potentially excellent probes for nucleic acid structure, function, and metabolism. Medicinally, they offer a unique source of opportunities for anticancer and antiviral therapy. With regard to this latter aspect, a number of "fat" nucleosides have recently exhibited potent, broad-spectrum antiviral and anticancer activities in vitro with little toxicity, if any, to the host cell lines. The antiviral activities include hepatitis B and C virus (HBV and HCV), West Nile virus (WNV), Epstein-Barr virus (EBV), Vericella Zoster virus (VZV), Japanese Encephalitis virus (JEV), Rhino virus (RV), Herpes Simplex (HSV-1 and HSV-2) viruses, and Measles virus (MV). The in vitro anticancer activities include leukemia, lung, colon, CNS, melanoma, ovarian, renal, prostate, and breast cancers. However, this proposal specifically focuses on the West Nile Virus (WNV) in light of the current health scare of this virus in US. The proposal concerns mechanistic investigations of viral replication employing a few "fat" nucleosides that have exhibited potent in vitro anti-WNV activity. Two specific modes viral inhibition, which are deemed most viable, will be explored. Appropriate synthetic strategies have been put in place for further structural modifications of "fat" nucleosides and nucleotides, contingent upon the outcome of the proposed mechanistic investigations, so as to eventually discover most potent antivirals against WNV with dismal, if any, human toxicity.